1. Field of the Invention
The present invention relates to N-substituted pyrroles, pyrazoles, imidazoles, triazoles and tetrazoles, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are useful for a variety of therapies, including treating and preventing cancer, inflammation, autoimmune diseases, pulmonary disease, septic shock, pain, preterm labor, weight loss disorders and infertility, and other diseases and disorders associated with MEK-1 and/or ERK-2.
2. Background
Chronic activation of the small G-protein Ras following growth factor signaling or activating mutations of H-, K- or N-Ras can lead to oncogenic transformations of several distinct cell types. M. Barbacid, Ann. Rev. Biochem., 56:779 (1987) and J. L. Bos, Cancer Res., 49:4682 (1989). Overexpression and/or activation of the MAP kinase ERK-2 is associated with several disease states that include cancer and a variety of immune disorders. V. S. Sivaram et al., J. Clin. Invest., 99:1478 (1997); G. Schett et al., Arthritis Rheum., 43:2501 (2000); E. Genot. Et al., Curr. Opin. Immunol., 12:289 (2000); S. Cowley et al., Cell, 77:841 (1994); and S. J. Mansour et al., Science, 265:966 (1994).
ERK-2 activation in such diseases is mediated by upstream activators MEK-1 (MAP kinase kinase), RAF-1 (MAP kinase kinase kinase) and Ras. See S. M. Thomas et al., Cell, 68:1031 (1992); and K. M. Wood et al., Cell, 68: 1041 (1992).
It would be desirable to have compositions that can modulate MEK-1 and/or ERK-2 activity.